It is often difficult to deliver compounds, such as proteins, peptides, nucleic acids and other drugs and diagnostic compounds intracellularly because cell membranes resist the passage of these compounds. It is even more difficult to target a specific type of cell for selective delivery of the compounds.
One method for transmembrane delivery of exogenous molecules is based on the mechanism of receptor-mediated endocytosis (RME). RME is a major mechanism of uptake of impermeant molecules by mammalian cells (Conner, S. D.; Schmid, S. L. Nature 2003, 422, 37-44). In this process, extracellular ligands bind cell surface receptors that cluster in dynamic regions of cellular plasma membranes. By actively pinching off to form intracellular vesicles, these membrane regions are internalized, encapsulating ligand-receptor complexes in the cytoplasm. These vesicles fuse and form early (primary/sorting) endosomes that are acidified (pH ˜6) by the activation of proton pumps, conditions that generally promote the dissociation of receptors from bound ligands. Free receptors often cycle back to the cell surface, generally via subsequent trafficking through related recycling endosomes (also termed the endocytic recycling compartment) (Maxfield, F. R.; McGraw, T. E. Nat. Rev. Mol. Cell. Biol. 2004, 5, 121-132). In contrast, free ligands are typically directed to more acidic late endosomes and lysosomes (pH {tilde over ( )}5), where hydrolases and other enzymes promote their degradation. Some viruses and other intracellular pathogens exploit RME to enter cells, but these organisms avoid degradation in lysosomes by expressing pH-dependent fusogenic proteins that disrupt endosomal membranes (Lakadamyali, M.; Rust, M. J.; Zhuang, X. Microbes Infect. 2004, 6, 929-836). To escape entrapment within these membranes and gain access to the cytosol, Semliki Forest virus disrupts early endosomes whereas influenza virus disrupts late endosomes during the course of infection. Nevertheless, many exogenous molecules that are introduced into cells using RME are not able to escape degradation in the late endosomes or the lysosome. Accordingly, endosomal disruption can facilitate delivery from the endosome into the cytosol of the cell.
Therefore, it would be advantageous to have a compound delivery platform that specifically targeted select cells and enabled endosomal escape to allow the compound to be received into cytosol of a specifically targeted cell.